Kidney disease is worldwide health problem that is becoming increasingly prevalent. Primary glomerular disease, both acquired and genetic, represents a significant proportion of these cases. We are interested in understanding the makeup of the glomerular filtration barrier and how it becomes damaged and leaky to plasma proteins. Our focus over the last sixteen years has been to investigate the composition and function of the glomerular basement membrane (GBM), a specialized extracellular matrix that is an integral component of the filtration barrier. The GBM contains laminin, collagen IV, nidogen, and the heparan sulfate proteoglycan agrin. Our studies of mice lacking the laminin beta2 chain suggests that the GBM itself serves as a barrier to albumin and protects podocytes from the injurious effects of plasma proteins, as mice lacking laminin beta2 develop nephrotic syndrome and renal failure. Mutations in human LAMB2 have also been shown to cause kidney disease; null mutations cause Pierson syndrome (congenital nephrotic syndrome with ocular and nervous system abnormalities), whereas missense mutations cause congenital nephrotic syndrome with less severe extrarenal manifestations. Our recent studies have shown that some of these missense mutations impair secretion of laminin-521 into the GBM, and that increased secretion of even mutant forms could be beneficial for patients carrying such mutations. The focus of this proposal is to find methods to ameliorate kidney disease in patients with GBM defects due to laminin abnormalities and to better understand the role of laminin polymerization in GBM structure and function. To accomplish this, we will 1) perform high throughput screens of drug libraries to find compounds that can promote secretion of mutant LAMB2 chains in vitro; 2) test these compounds in vivo in our mouse models expressing mutant laminin beta2 chains to look for improved secretion and an improved filtration barrier; and 3) characterize activity and function of a human LAMB2 mutation that affects laminin polymerization. The results of these studies will provide important new insights into laminin and basement membrane biology and lead to potential therapies for human glomerular disease involving GBM defects.